1. Technical Field
The invention relates to an improved process for the preparation of macrocyclic compounds useful as agents for the treatment of hepatitis C viral (HCV) infections.
2. Background Information
The macrocyclic compounds of the following formula (I) and methods for their preparation are disclosed in the following patent applications and publications: Llinas Brunet et al, U.S. Patent Application Publication No. 2005/0080005 A1; Samstag et al, U.S. Patent Application Publication No. 2004/0248779 A1 and Busacca et al, U.S. application Ser. No. 11/078,074, filed Mar. 11, 2005:
wherein Het is a five-, six- or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur; said heterocycle being substituted with R1 at any available position on the heterocycle;    R1 is selected from R20, —NR22COR20, —NR22COOR20—NR22R21 and —NR22 CONR21 R23, wherein    R20 is selected from (C1-8)alkyl, (C3-7)cycloalkyl and (C3-7)cycloalkyl(C1-4)alkyl-, wherein said cycloalkyl or cycloalkylalkyl may be mono-, di- or tri-substituted with (C1-3)alkyl;    R21 is H or has one of the meanings of R20 as defined above,    R22 and R23 are independently selected from H and methyl,    each Alk is independently a C1-C6 alkyl group;    R3 is hydroxy, NH2, or a group of formula —NH—R9, wherein R9 is C6 or C10 aryl, heteroaryl, —C(O)—R10, —C(O)—NHR10 or —C(O)—OR10,            wherein R10 is C1-6 alkyl or C3-6 cycloalkyl;            D is a 3 to 7-atom saturated alkylene chain;    R4 is H, or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, or C1-6 thioalkyl; and    A is an amide of formula —C(O)—NH—R11, wherein R11 is selected from the group consisting of: C1-8 alkyl, C3-6 cycloalkyl, C6 or C10 aryl, C7-16 aralkyl and SO2R11A wherein R11A is C1-8 alkyl, C3-7 cycloalkyl or C1-6 alkyl-C3-7 cycloalkyl;    or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof;
The compounds of formula (I) are disclosed in the above-mentioned patent documents as being active agents for the treatment of hepatitis C viral (HCV) infections and can be used for said treatment indication as described therein. The problem addressed by the present invention is to provide highly convergent processes which allow for the manufacture of these compounds with a minimum number of steps and with sufficient overall yield.